As injectable compositions comprising a 2-[(2-pyridyl)methylsulfinyl]benzimidazole compound having an antiulcer action, for example, the following injectable compositions have been reported.
1) Japanese Patent Application Laid-Open No. 138213/1990 (JP-2-138213A) (EP 0356143) discloses an injectable solution which comprises a benzimidazole compound having an antiulcer action and at least one of ethanol, propylene glycol and polyethylene glycol. The literature also discloses an injectable solution which contains a freeze-dried product of the benzimidazole compound dissolved in a mixture solution of an acidic substance and a polyethylene glycol, and further contains a saccharide such as mannitol and N-methylglucamine. Further, in Example 4 of the literature, 1 g of lansoprazole was dispersed in a distilled water for injection, and 3 ml of 1N-aqueous sodium hydroxide solution was added thereto to dissolve lansoprazole, followed by addition of water to make up to the total of 50 ml. The mixture was subjected to sterile filtration. The resulting filtrate was filled in a portion into vials, followed by lyophilization. The lyophilized powder was dissolved in a dissolving solvent composed of N-methylglucamine, hydrochloric acid and a polyethylene glycol.
However, in the injectable solution, the specific liquid composition for dissolution containing an alcohol selected from ethanol, propylene glycol and a polyethylene glycol is required, and an excess of alkali (sodium hydroxide) is employed.
2) Japanese Patent Application Laid-Open No. 92853/1994 (JP-6-92853A) (WO94/02141) discloses an injection comprising a 2-[(2-pyridyl)methylsulfinyl]benzimidazole compound having an antiulcer activity or a salt thereof and an aqueous solvent without nonaqueous solvent, wherein the pH of the injection is not less than 9.5 and not more than 11.5. In Example of the literature, 1N sodium hydroxide (2.3 ml) is added to 21.3 g of sodium salt of omeprazole (20 g as omeprazole), and a water for injection is added thereto to adjust the pH to 11.5. After filtration for sterilization, this alkaline aqueous solution is charged in vials and is lyophilized, followed by dissolution of the lyophilized product in a physiological saline to give an omeprazole injection.
However, an excess of an alkali (sodium hydroxide) is employed in the injection with the use of an aqueous solvent containing no nonaqueous solvent. Thus, in order to prepare an injection solution with the use of a freeze-dried injection, such complicated operations are required as kneading a 2-[(2-pyridyl)methylsulfinyl]benzimidazole compound for wetting and then dissolving the compound. The kneading operation might cause the formation of an exogenous material due to contact of the using instruments with each other. Moreover, owing to the complicated operations, it takes many hours to dissolve, as a result, the high concentration of an alkali aqueous solution is contacted with carbon dioxide in an air to decrease pH of the solution so that the quality of the injection is sometimes deteriorated. Further, there is a possibility that an excess of an alkali causes a pain or dolor and a local irritation by an injection. Therefore, there has been a growing demand for such an injectable composition that there is no need to attach the exclusive dissolving solution for the injectable composition, that the amount of an alkali to be used is as small as possible, and that the kneading operation and the complicated dissolving operation are not required. Moreover, such injectable compositions are considerably needed as preventing pH of the injectable composition from decreasing upon producing and redissolving of the injectable composition, and as maintaining the quality of the injectable composition.
It is, therefore, an object of the present invention to provide an injectable composition having no need to attach the exclusive dissolving solution for the injectable composition and capable of being dissolved in or diluted with a physiological saline or an infusion solution, and a production process of the same.
Another object of the present invention is to provide an injectable composition dissolvable by a simple operation, and a production process of the same.
Still another object of the present invention is to provide such an excellent injectable composition that pH of the injectable composition does not decline and that a pain (or dolor) or a local irritation is relieved by decreasing the alkali amount to be used, and a production process of the same.